The present invention relates to novel therapeutic methods and pharmaceutical compositions for treating conditions associated with inhibition of interleukin-converting enzyme (ICE).
Cytokines play an important role in a regulation of the immune system. Several studies indicate that variations in cytokine expression are associated with disease activity in immune mediated or inflammatory disorders, including autoimmune disorders (Acta. Univ. Palacki. Olomuc., Fac. Med. 143: 19-29, 2000; Rheumatol. 39: 1078, 2000; J. Immunol. 167: 5338, 2001), trauma (surgery) (Blood 87: 2095-2147, 1996), ischemic diseases (myocardial infarction) (Acta. Univ. Palacki. Olomuc., Fac. Med. 143: 19-29, 2000; Cell. Immunol. 184: 12, 1998), Alzheimer's disease (Blood 87: 2095-2147, 1996), liver diseases (Immunol. Rev. 174: 192-209, 2000), rheumatoid arthritis (Arthritis Rheum. 44: 275, 2001; J. Rheumatol. 28: 1779, 2001), obesity (Shock 14: 253, 2000), psoriasis (Arch. Dermatol. Res. 293: 334, 2001), and sepsis (Acta. Univ. Palacki. Olomuc., Fac. Med. 143: 19-29, 2000; Blood 87: 2095-2147, 1996; Shock 16: 441, 2000; J. Med. 31: 15, 2000).
The sepsis syndrome is an excessive, acute inflammatory response to a variety of noxious insults, particularly bacterial infection. The role of cytokines in the pathogenesis of sepsis is complex since both deficient and excessive immune responses have been associated with this syndrome. Pro-inflammatory cytokines are, on the one hand, required locally for effective anti-bacterial effector mechanisms (J. Immunol. 145: 3762, 1990; Nature 381: 75, 1996; and Infect. Immun. 64: 5211, 1996), but on the other hand they are potentially toxic when secreted into the circulation (Nature 330: 662, 1987; J. Clin. Invest. 89: 1551, 1992). Therefore, the ability to inhibit the production of highly active inflammatory mediators may have a beneficial effect in controlling the development of sepsis. Patients with septic shock who died had higher levels of IL-18 than patients who survived (Shock 14: 253, 2000).
IL-1β is crucial for the induction of fever and acute-phase response during local tissue damage; in systemic inflammation it contributes to inflammatory reaction (Acta. Univ. Palacki. Olomuc., Fac. Med. 143: 19-29, 2000). This cytokine is important in response to tissue damage and infection, but is not required for normal development and homeostasis. Serum levels of IL-1β and IL-1Ra are significantly elevated in severe sepsis (Acta. Univ. Palacki. Olomuc., Fac. Med. 143: 19-29, 2000).
The IL-1 family of cytokines, which include IL-18 and IL-1β, are key hormones of the immune system. Both IL-18 and IL-1β are expressed and produced by various types of cells from hematopoetic and nonhematopoetic lineages, such as dendritic cells, monocytes/macrophages, microglia cells, keratinocytes, intestinal epithelial cells, etc. Recent studies emphasize the pathophysiological role of IL-18 and IL-1β in a variety of neurodegenerative, autoimmune and inflammatory diseases, such as inflammation, hematopoiesis and wound healing (Immunol. Today 7: 45-56, 1986).
Interleukin-18 is an early signal in the development of T-lymphocyte helper type 1 (Th1) responses. It acts together with IL-12 to induce various cytokines, including IFN-γ, to activate Th1 cells. IFN-γ is in turn responsible for inducing production of the soluble receptor protein, IL-18 binding protein (IL-18BP), a native down-regulator of IL-18 activity, which specifically binds IL-18 and neutralizes its biological activity in vitro and in vivo (Immunity 10: 127, 1999).
IL-18 and IL-1γ are expressed and produced in an inactive form, which requires activation by protease enzymes. The protease enzymes are divided into four families, (serine-, metallo-, aspartic- and cystein-proteases) based on their catalytic residues and mechanism of action. Whereas serine proteases utilize a nucleophilic hydroxyl of the serine residue and aspartic and metalloproteases posses carboxylates as active functionalities, the cysteine proteases have an active-site thiol-nucleophile.
The caspase enzymes (Cysteine Aspartic-Specific Proteases) are a family of intracellular cysteine endopepetidases, which cleave their substrates after aspartate residues (Ann. Rev. Immunol. 17: 781-828, 1999). The caspases are divided into two classes, based on the lengths of their N-terminal prodomains. Caspases-1, -2, -4, -5, -8, and -10 have long prodomains; and caspases-3, -6, -7, and -9 have short prodomains.
Caspase 1, which is also known and referred to herein, interchangeably, as interleukin-β-converting enzyme (ICE), is expressed as a proenzyme of 45 kD in many tissues (J. Clin. Immunol. 19:1, 1999). Upon stimulation, it undergoes activation by proteolytic cleavage. Active ICE is a tetramer of two non-identical subunits p10 and p20 in 2:2 proportion, which is uniquely responsible for cleaving pro-interleukin-1β (31 or 33 kD), into mature interleukin-1β (IL-1β) (17.5 kD), which consists of the C-terminal 153 residues of the inactive form; and pro-IL-18 (24 kD), which is cleaved at Asp35, into the biologically active 18 kD form (J. Immunother. 25: S4-S11, 2002; Nature 386: 619, 1997, Science 275: 206, 1997). The active cytokine is then released by a non-standard mechanism, since unlike the case with most secretory proteins, the precursor lacks a signal sequence and is not associated with membrane-bound compartments (J. Exp. Med. 167: 389-407, 1988).
ICE therefore plays an important role in physiological processes mediated by IL-1β and IL-18.
Various tellurium compounds have been described in the art as having immunomodulating properties. A particularly effective family of tellurium-containing compounds is taught, for example, in U.S. Pat. Nos. 4,752,614; 4,761,490; 4,764,461 and 4,929,739, whereby another effective family is taught, for example, in a recently filed U.S. Provisional Patent Application No. 60/610,660, which are all incorporated by reference as if fully set forth herein. The immunomodulating properties of this family of tellurium-containing compounds is described, for example, in U.S. Pat. Nos. 4,962,207, 5,093,135, 5,102,908 and 5,213,899, which are all incorporated by reference as if fully set forth herein.
One of the most promising compounds described in these patents is ammonium trichloro(dioxyethylene-O,O′)tellurate, which is also referred to herein and in the art as AS101. AS101, as a representative example of the family of tellurium-containing compound discussed hereinabove, exhibits antiviral (Nat. Immun. Cell Growth Regul. 7(3):163-8, 1988; AIDS Res Hum Retroviruses. 8(5):613-23, 1992), and tumoricidal activity (Nature 330(6144):173-6, 1987; J. Clin. Oncol. 13(9):2342-53, 1995; J. Immunol. 161(7):3536-42, 1998).
It has been suggested that AS101, as well as other tellurium-containing immunomodulators, stimulate the innate and acquired arm of the immune response. For example, it has been shown that AS101 is a potent activator of interferon (IFN) in mice (J. Natl. Cancer Inst. 88(18):1276-84, 1996) and humans (Nat. Immun. Cell Growth Regul. 9(3):182-90, 1990; Immunology 70(4):473-7, 1990; J. Natl. Cancer Inst. 88(18):1276-84, 1996.)
It has also been demonstrated that AS101 induces the secretion of a spectrum of cytokines, such as IL-1, IL-6 and TNF-α, and that macrophages are one main target for AS101 (Exp. Hematol 23(13):1358-66, 1995). AS101 was also found to inhibit IL-10 at the m-RNA level, which may cause an increase in IL-12 and IFN-γ (Cell Immunol 176(2):180-5, 1997; J. Natl. Cancer Inst. 88(18):1276-84, 1996).
Other publications describing the immunomodulation properties of AS101 include, for example, “The immunomodulator AS101 restores T(H1) type of response suppressed by Babesia rodhaini in BALB/c mice”. Cell Immunol 1998 February; “Predominance of TH1 response in tumor-bearing mice and cancer patients treated with AS101”. J Natl Cancer Inst 1996 September; “AS-101: a modulator of in vitro T-cell proliferation”. Anticancer Drugs 1993 June; “The immunomodulator AS101 administered orally as a chemoprotective and radioprotective agent”. Int J Immunopharmacol 1992 May; “Inhibition of the reverse transcriptase activity and replication of human immunodeficiency virus type 1 by AS 101 in vitro”. AIDS Res Hum Retroviruses 1992 May; “Immunomodulatory effects of AS101 on interleukin-2 production and T-lymphocyte function of lymphocytes treated with psoralens and ultraviolet A”. Photodermatol Photoimmunol Photomed 1992 February; “Use and mechanism of action of AS101 in protecting bone marrow colony forming units-granulocyte-macrophage following purging with ASTA-Z 7557”. Cancer Res 1991 Oct. 15; “The effect of the immunomodulator agent AS101 on interleukin-2 production in systemic lupus erythematosus (SLE) induced in mice by a pathogenic anti-DNA antibody”. Clin Exp Immunol 1990 March; “Toxicity study in rats of a tellurium based immunomodulating drug, AS-101: a potential drug for AIDS and cancer patients”. Arch Toxicol 1989; “The biological activity and immunotherapeutic properties of AS-101, a synthetic organotellurium compound”. Nat Immun Cell Growth Regul 1988; and “A new immunomodulating compound (AS-101) with potential therapeutic application”. Nature 1987 November.
AS-101 has also been shown to have protective effects against lethal and sublethal effects of irradiation and chemotherapy (Blood 85: 1555, 1995; J. Nat. Cancer Inst. 88: 1276, 1996; In. J. Cancer 86: 281, 2000; J. Immunol. 156: 1101, 1996; J. Immunol. 145: 1507, 1990; Cancer Res. 51: 1499, 1991).
Moreover, AS101 can inhibit activity of STAT3 (Signal Transducer and Activator of Transcription 3) via IL-10 inhibition (Cancer Res. 64: 1843, 2004). When binding of IL-10 to the IL-10 receptor occurs, receptor-associated Janus activated kinase (Jak) tyrosin kinases are activated and stimulate downstream signaling. One of the main transcription factors being activated is STAT3. Activated, phosphorylated STAT3 is translocated to the nucleus and regulates specific gene expression (J. Immunol. 155: 1079, 1995). One of the target genes for STAT3 is vascular endothelial growth factor (VEGF) (Clin. Cancer Res. 8: 945, 2002; Oncogene 21: 2000, 2002; Oncogene 22: 319, 2003). This factor recently was found to be responsible for IL-18 induction (Cancer Res. 64: 304, 2004). Moreover, recently it was found that IL-1β alone (Cancer Sci. 94: 244, 2003) and together with oncostatin-M (Oncogene 22: 8117, 2003) induces up to sevenfold higher VEGF expression due to their mutual influence on STAT3. The ability of AS101 to down-regulate STAT3, may contribute to the overall inhibitory effect.
Furthermore, it was found that although AS101 shows no inhibition of serine, metallo, and aspartic proteases, it inhibits cysteine proteases, via a catalytic thiol oxidation (Inorg. Chem. 37: 1704-1712, 1998).
In addition to its immunomodulatory effect, AS101 is also characterized by low toxicity. Toxicity tests have shown that LD50 values in rats following intravenous and intramuscular administration of AS101 are 500-1000 folds higher than the immunologically effective dose.
Hence, while the prior art teaches various primary and secondary roles of tellurium-containing compounds such as AS101 as immunomodulators, it fails to teach the involvement of tellurium-containing compounds in inhibition of caspase-1/IL-1β-converting enzyme (ICE).
In view of the findings that a myriad of medical conditions is associated with ICE, there is a widely recognized need for and it would be highly advantageous to have, novel agents that are capable of inhibiting ICE and hence can be beneficially utilized in the treatment of such conditions.